One of the most puzzling phenomena in modern physiology is the existence of fractal patterns in a wide range of physiological systems (i.e., the structure of fluctuations are similar or indistinguishable at different time scales). The physiological importance of fractal control is demonstrated in numerous studies and exemplified by reduced fractal cardiac and activity controls with aging and under pathological conditions, and most importantly, by the predictive value of reduced fractal cardiac control for decreased survival. Fractal physiology appears to impart some adaptive advantage, and in this context, the existence of fractal patterns challenges the traditional theory of homeostasis of maintaining physiologic constancy. Despite the clear importance of this fractal phenomenon, to date, no underlying mechanism has been established for fractal control in any neural or physiological system. The PI's recent studies indicate that the endogenous circadian system is critically involved in the fractal control of motor activity at multiple time scales. The proposal will formally assess the physiological significance and the neurobiological basis of the fractal regulatory function of the circadian system. The primary goal is to identify the neuronal nodes and pathways through which the circadian system imparts fractal activity control. To complement the PI's established expertise in fractal physiology, the proposal outlines two years of multidisciplinary training in circadian biology, human physiology/pathology, neurobiology, system biology under supervision of three highly regarded scientists in these fields. The training will enable the PI to acquire the requisite skills necessary for a sustainable and prolific career in the interdisciplinary field of circadian biology and fractal physiology. The subsequent three years of the independent research phase will allow the PI to achieve the main research goal and help establish the PI as an independent researcher in the field. The specific aims are 1) to determine the effects of changes in the central circadian system on fractal activity control;2) to determine the effects of circadian misalignment on fractal activity control;and 3) to identify and validate neuronal node(s) in the activity control network and their interactions that contribute to fractal activity control. Achieving these aims will provide the neurophysiologic basis for the first model of fractal control. Better understanding of the neuronal circuitry involving in circadian and activity regulation ought to provide useful guidance for improved diagnosis and treatment of circadian-related sleep and behavioral disturbances. PUBLIC HEALTH RELEVANCE: This project is aimed at understanding the neurophysiological mechanisms causing fractal patterns of activity (i.e., why the structure of activity fluctuations are indistinguishable at different time scales). Better understanding of the neuronal circuitry involving in activity regulation ought to provide useful guidance for improved diagnosis and treatment of circadian-related sleep and behavioral disturbances.